An intact hypothalamic-pituitary-adrenal axis responds to stress in mammals. Mediation of the response takes place by secretion of cortocotropin-releasing hormone (CRH) by the paraventricular nucleus of the hypothalamus. CRH is a 41-amino acid peptide derived by enzymatic cleavage from a 191-amino acid preprohormone. Shibahara et al. (1983)cloned and sequenced the human CRH gene. Arbiser et al. (1988) assigned the gene for CRH to 8q13 by somatic cell hybrid and in situ hybridization studies. The absence of secondary hybridization strongly suggested that hypothalamic and placental CRH are transcribed from the same gene. Knapp et al. (1993) showed that the homologous gene is located on mouse chromosome 3.
NCBI Summary:
This gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition. [provided by RefSeq, Nov 2015]
General function
Ligand, Hormone
Comment
Cellular localization
Comment
Somatostatin treatment reduces the exaggerated response of adrenocorticotropin hormone and cortisol to corticotropin-releasing hormone in polycystic ovary syndrome. Lanzone A et al. (1997) To evaluate the influence of somatostatin analogue (octreotide) in the function of hypothalamic-pituitary-adrenal (HPA) axis in women with polycystic ovary syndrome (PCOS). Women referred to the Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore. Twelve PCOS women and 12 normo-ovulatory controls. In early follicular phase, I microgram/kg human corticotrophin-releasing hormone (CRH) was injected at 9:00 A.M. and blood samples were collected for 90 minutes after stimulus; ACTH and cortisol plasma levels were measured. The following day at 8:00 A.M., PCOS patients received an ACTH test (250 micrograms IV) and samples were collected 60 minutes after injection. After 6 weeks of octreotide treatment (100 mg s.c. twice daily), PCOS patients repeated the same study. Plasma cortisol and ACTH concentrations. The ACTH and cortisol baseline levels were similar in PCOS and control patients. The responses to human CRH of ACTH (incremental area = 437.86 +/- 188.7 versus 175.78 +/- 87.6 pmol/L; mean +/- SD) and cortisol (incremental area = 17,293.6 +/- 4,320.3 versus 5,885 (912.1 nmol/L) were significantly greater in PCOS with respect to control subjects. After octreotide treatment, ACTH response significantly decreased and no difference was observed with respect to controls (incremental area = 176.94 +/- 91.4). Cortisol responses were decreased by treatment. However, they remained significantly higher than in controls. Treatment did not modify adrenal response to IV ACTH. Data suggest that, in the HPA axis, hyperfunction of PCOS somatostatin could be involved partially.//////////////////
Restraint-induced CRH elevation triggers apoptosis of ovarian cells and impairs oocyte competence via activation of the Fas/FasL system. Li CY et al. (2018) Mechanisms by which psychological stress damages oocytes are largely undetermined. Although a previous study showed that the stress-induced corticotrophin-releasing hormone (CRH) elevation impaired oocyte competence by triggering apoptosis of ovarian cells, how CRH causes apoptosis in ovarian cells and oocytes is unknown. In this study, we have examined the hypothesis that restraint stress (RS)-induced CRH elevation triggers apoptosis of ovarian cells and impairs oocyte competence through activating the Fas/FasL system. The results showed that RS of female mice impaired oocyte competence, enhanced expression of CRH and CRH receptor (CRH-R) in the ovary, and induced apoptosis while activating the Fas/FasL system in mural granulosa cells (MGCs) and oocytes. Injecting mice with CRH-R1 antagonist antalarmin significantly alleviated the adverse effect of RS on oocyte developmental potential. Treatment of cultured MGCs recapitulated the effects of CRH and antalarmin on apoptosis and Fas/FasL expression in MGCs. Silencing FasL gene by RNA interference in cultured MGCs further confirmed the involvement of the Fas/FasL system in the CRH triggered-apoptosis of ovarian cells. It is concluded that the RS-induced CRH elevation triggers apoptosis of ovarian cells and impairs oocyte competence via activation of the Fas/FasL system.//////////////////
Restraint Stress Impairs Oocyte Developmental Potential: Role of CRH-Induced Apoptosis of Ovarian Cells. Liang B 2013 et al.
This study examined the role of CRH-induced ovarian cell apoptosis in the restraint stress (RS)-induced impairment of oocyte competence. Oocyte percentages of apoptotic cumulus cells (CCs) did not differ between stressed and control mice before in vitro maturation (IVM) but became significantly higher in stressed mice after IVM without serum, growth factor and hormone. The level of Bcl2 mRNA decreased significantly in mural granulosa cells (MGCs) and ovarian homogenates after RS. Whereas ovarian estradiol, testosterone and IGF1 decreased, cortisol and progesterone increased significantly following RS. RS increased the level of CRH in serum, ovary and oocyte while enhancing the expression of CRHR1 in CCs, MGCs and thecal cells. RS down-regulated ovarian expression of glucocorticoid receptor (GR) and brain-derived neurotrophic factor. Furthermore, CRH supplementation to IVM medium impaired oocyte developmental potential while increasing apoptotic CCs, an effect that was completely overcome by addition of CRHR1 antagonist antalarmin. Results suggested that RS impaired oocyte competence by increasing CRH but not glucocorticoids. Increased CRH initiated a latent apoptotic program in CCs and oocytes during their intra-ovarian development, which was executed later during IVM to impair oocyte competence. Thus, elevated CRH interacted with increased CRHR1 on thecal cells and MGCs reducing the production of testosterone, estrogen and IGF1 while increasing the level of progesterone. The imbalance between estrogen and progesterone and the decreased availability of growth factors triggered apoptosis of MGCs and facilitated CCs expression of CRHR1, which interact with the oocyte-derived CRH later during IVM to induce CCs apoptosis and reduce oocyte competence.
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The Effect of CRH and Its Inhibitor, Antalarmin, on in Vitro Growth of Preantral Mouse Follicles, Early Embryo Development, and Steroidogenesis. Dinopoulou V et al. In vitro growth systems of preantral follicles allow studying the effect of various endocrine, paracrine, and autocrine factors on follicular growth and oocyte maturation. CRH is a 41-amino-acid neuropeptide responsible for endocrine, autonomic, immunological, and behavioral responses of mammals to stress and has two receptors, CRH receptor type 1 (CRH-R1) and CRH-R2. Antalarmin, a CRH-R1 antagonist, has been used to elucidate the role of CRH in stress, inflammation, and reproduction. The present study describes in vitro growth of mouse preantral follicles, early embryo development, and steroidogenesis in the presence of CRH and its antagonist antalarmin. We cultured 732 follicles in control media, 1306 in CRH 10(-7) mol/liter, and 1202 in CRH 10(-7) plus antalarmin 10(-6) mol/liter. The culture medium was assayed on alternate days for 17?estradiol, progesterone, and ?human chorionic gonadotropin. Total RNA was extracted from preantral follicles as well as early preimplantation embryos and was assessed by real-time RT-PCR for the expression of CRH-R1 and CRH-R2 mRNAs. Hormone analysis showed that the CRH group had lower levels of 17?estradiol, progesterone, and ?human chorionic gonadotropin as the culture progressed, in comparison with the other two groups. RT-PCR demonstrated the presence of CRH-R1 and CRH-R2 in all stages of preantral follicle culture. Morula/blastocyst-stage embryos expressed only CRH-R1. In conclusion, CRH has an inhibitory effect on in vitro fertilized oocytes, resulting from cultured preantral follicles at all stages of preimplantation embryo development. Furthermore, the presence of CRH in the culture medium inhibits steroidogenesis by preantral mouse follicles cultured in vitro.
Corticotropin-releasing hormone inhibits in vitro oocyte maturation in mice. Kiapekou E et al. The expression of corticotropin-releasing hormone (CRH) receptor 1 messenger RNA in stages of follicle growth was examined by reverse transcriptase-polymerase chain reaction in long-term cultures of early preantral mouse follicles with and without CRH addition. Corticotropin-releasing hormone receptor 1 is present in stages of mouse follicle growth, whereas 10(-9), 10(-7), and 10(-6) mol/L CRH inhibits oocyte maturation in vitro, an effect reversed by antalarmin addition.
Ghizzoni et al. (1997) found that CRH exerts a CRH- and IL-1 receptor-mediated inhibitory effect on ovarian steroidogenesis and might be actively involved in the still enigmatic processes of follicular atresia and luteolysis. Ghizzoni L, et al 1997 reported that corticotropin-releasing hormone (CRH) inhibits steroid biosynthesis by cultured human granulosa-lutein cells in a CRH
and interleukin-1 receptor-mediated fashion. The
effects of graded doses of ovine CRH were evaluated in the
conditioned medium obtained after 24 h incubation of the cells. All CRH
concentrations employed except for the lowest one caused a
significant decrease of media E2 and P4 levels. The alpha-helical
CRH9-41 antagonist blocked the suppressive effect
of 10(-9) mol/liter CRH on both E2 and P4 secretion, while it had no effect when
added to the culture media without CRH. Since interleukin (IL-1)-1 mediates
certain actions of CRH on leukocytes, they examined whether the CRH effect on
ovarian steroidogenesis was IL-1-mediated. Interleukin-1 receptor antagonist at
10(-7) and 10(-6) mol/liter blocked the inhibitory effects of CRH on E2 and P4
secretion, while it had no effect in the absence of CRH. In conclusion, CRH exerts
a CRH- and IL-1 receptor-mediated inhibitory effect on ovarian steroidogenesis
and might be actively involved in the still enigmatic processes of follicular atresia
and luteolysis.
Calogero AE, et al 1996 reported the effects of corticotropin-releasing hormone on ovarian estrogen production in vitro.
CRH inhibited FSH-stimulated estrogen production from rat
granulosa cells in a dose-dependent fashion. The maximal effect was achieved at
a concentration of 10(-8) M, which suppressed estrogen production by about 30%. Low concentrations of CRH (10(-10) M), incapable of modulating maximal
estrogen production in response to FSH, provoked a right-ward shift of the
estrogen dose-response curve to FSH. CRH (10(-8) M) suppressed the production
of tritiated water (equivalent to estrogen production) from homogenates of rat
granulosa cells incubated with a half-maximal concentration of FSH. Basal
estrogen production by human granulosa-luteal cells was also inhibited by CRH at
a concentration of 10(-10) M. The maximal effect was achieved with a
concentration of 10(-8) M, which lowered estrogen production by 25%. The CRH
receptor antagonist alpha-helical CRH-(9-41) antagonized the inhibitory effect of CRH on estrogen production from rat granulosa and human granulosa-luteal cells,
whereas alone it had no effect. CRH did not have any effect on the intracellular
cAMP content of rat granulosa and human granulosa-luteal cells. Calogero AE, et al reported that Corticotrophin-releasing hormone inhibits insulin-like growth
factor-I release from primary cultures of rat granulosa cells.
Expression regulated by
mir375
Comment
MiR-375 Mediates CRH Signaling Pathway in Inhibiting E2 Synthesis in Porcine Ovary. Yu C et al. (2016) The corticotropin-releasing hormone (CRH) signaling system is involved in numbers of stress-related physiological and pathological responses，including its inhibiting effects on estradiol (E2) synthesis and follicular development in the ovary. In addition, there are reports that microRNAs (miRNAs) can control the function of animal reproductive system. The aim of present study was to investigate the functions of miR-375 and the relationship between miR-375 and CRH signaling molecules in the porcine ovary. First, our common PCR results show that miR-375 and the CRH receptor 1 (CRHR1) are expressed in porcine ovary, whereas CRH receptor 2 (CRHR2) is not detected. We further have located the cell types of miR-375 and CRHR1 by in situ hybridization (ISH), and the results show that miR-375 is located only in the granulosa cells, whereas CRHR1 is positive in all of granulosa cells and oocytes, inferring that miR-375 and CRHR1 are co-localized in granulosa cells. Second, we show that overexpression of miR-375 in cultured granulosa cells suppresses the E2 production, while miR-375 knockdown demonstrates the opposite result. Besides, our in vitro results demonstrate that miR-375 mediates the signaling pathway of CRH inhibiting E2 synthesis. Finally, our data show that the action of miR-375 is accomplished by directly binding to the 3'UTR of specificity protein1 (SP1) mRNA to decrease the SP1 protein level. Thus, we conclude that miR-375 is a key factor in regulating E2 synthesis by mediating the CRH signaling pathway.//////////////////
Ovarian localization
Theca, Luteal cells, Stromal cells
Comment
Ghizzoni et al. (1997) determined that CRH immunoreactivity was localized by immunohistochemistry in the cytoplasm of thecal cells surrounding the ovarian follicles, in luteinized cells of the stroma, and in large granulosa-derived luteinized cells of developing corpora lutea. Mastorakos G, et al 1993 reported immunoreactive corticotropin-releasing hormone and its binding
sites in the rat ovary.
They
detected cytoplasmic immunoreactive CRH (IrCRH) in theca and stromal cells
and in cells within the corpora lutea, at all phases of the estrous cycle. Using a
specific radioimmunoassay, they measured IrCRH in extracts of rat ovaries
(0.042-0.126 pmol/g wet tissue). The mobility of the ovarian IrCRH molecule
was similar to that of rat/human CRH by reverse phase HPLC.
Mastorakos G, et al 1994 reported the presence of immunoreactive corticotropin-releasing hormone in
normal and polycystic human ovaries.
Immunoreactivity was intense in the cytoplasm of
thecal cells surrounding the ovarian follicles, in luteinized cells of the stroma, and in a subpopulation of cells within the corpora lutea. No IrCRH was present in
oocytes of primordial follicles. Polycystic ovaries also had IrCRH in thecal cells;
however, CRH immunostaining was less prominent or completely absent from the stroma or the sparsely present corpora lutea and was clearly detected in oocytes of primordial follicles.
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: To find the importance of CRH in the response of the hypothalamic-pituitary-adrenal axis to stress and its role in fetal development, Muglia et al. (1995) constructed a mouse model of CRH deficiency by targeted mutation in embryonic stem cells. They reported that CRH-deficient mice reveal a fetal glucocorticoid requirement for lung maturation. Postnatally, however, despite marked glucocorticoid deficiency, the mice exhibited normal growth, fertility, and longevity, suggesting that the major role of glucocorticoid occurs during fetal, rather than postnatal, life.